CHANGES IN VASCULAR ALPHA-ADRENERGIC RECEPTOR MECHANISMS DURING MATURATION.

Abstract

The premature infant is subject to pathological alterations of the cardiovascular system leading to insufficient pulmonary blood flow and/or sudden surges of pressure to fragile cerebral blood vessels, conditions which are often associated with hypotension. Dobutamine appears to be a potentially useful agent to increase pulmonary blood flow and correct hypotension. In view of this potential, the alpha-adrenergic characteristics of dobutamine acts were studied in the isolated rabbit femoral and pulmonary arteries. Dobutamine on the post synaptic membrane of these tissues as a high affinity, low intrinsic activity alpha adrenergic agonist. No action of dobutamine to modulate stimulation evoked release of norepinephrine was found, although dobutamine did increase spontaneous release of norepinephrine. This effect was not blocked by antagonists of uptake 1 and uptake 2. To further evaluate dobutamine for use in the neonate, contractile responses of the femoral and pulmonary arteries and aorta to dobutamine and norepinephrine were studied in dogs of various ages from newborn to 6 weeks. Maximal contractile responses to norepinephrine in the pulmonary artery and aorta increased with age. Dobutamine produced small or no responses in all newborn tissues studied and also showed increasing responsiveness with age. To allow future study of the mechanism of these changes a method of radioligand binding was established for vascular smooth muscle using the ligands prazosin and rauwolscine in the dog and rabbit pulmonary artery and aorta. This binding was found to demonstrate the properties of saturability, sterospecificity and rank order of potency. Possible variables that could account for the observed changes in response during maturation were mathematically modeled to provide a theoretical basis for future studies combining measurement of contractile response and radioligand binding techniques.